Drug-coated medical devices

ABSTRACT

A medical device includes a body defining an exterior surface, and a coating including a therapeutic agent-containing nanoparticle disposed on the exterior surface of the medical device. The nanoparticle may include a brush-arm star polymer. The therapeutic agent may be paclitaxel.

FIELD

The present disclosure relates to, among other things, medical devicessuch as inflatable balloon catheters; and more particularly todrug-coated medical devices.

TECHNICAL BACKGROUND

Vascular atherosclerotic lesions that create arterial luminal narrowingare typically treated in angioplasty procedures via catheters providedwith an inflatable balloon. The catheter is advanced, typicallyfollowing a guidewire, to an opening within the atherosclerotic lesionof the narrowed artery. Once the inflatable balloon has been arranged atthe artery narrowing, it may be inflated and deflated, sometimesrepeatedly. The inflation, with successive deflation, of the inflatableballoon within the artery can reduce the extent of the arterial luminalnarrowing, and restore a suitable blood flow.

In many cases, patients develop a re-narrowing of the vessel lumen atthe intervention point within a few months. Such re-narrowing, orrestenosis, is due to a cell hyperproliferation process, particularly ofthe vascular smooth muscle cells, and may be due to the dilating actioncaused by the inflatable balloon.

Inflatable balloons or stents can be coated with a drug havinganti-proliferative action to prevent or retard restenosis. Among thedrugs usually employed to such aim, paclitaxel (taxol) has proved to beparticularly efficient.

However, with current therapies the paclitaxel delivered by the ballooncatheter to the wall of the vessel drops below an effectiveconcentration after a period of time. For example, the paclitaxel may bepresent on the vessel wall in an effective anti-proliferativeconcentration for about 6 months following treatment. It may bedesirable to increase the amount of time that paclitaxel is present atthe vessel wall in an effective concentration.

BRIEF SUMMARY

Described herein, among other things, is a medical device on which acoating comprising at least one nanoparticle containing a therapeuticagent is disposed. The medical device is configured to deliver thenanoparticle to a wall of a vessel of the patient. For example, themedical device may comprise a coated balloon that when inflated in avessel of a patient may deliver the nanoparticles to the wall of thevessel. The therapeutic agent may be released from the nanoparticlesover time. Accordingly, the use of nanoparticles as described herein mayprolong the duration over which the therapeutic agent is present in thevessel wall at an effective concentration relative to medical devicescoated with the therapeutic agent without the nanoparticle.

The nanoparticle-coated medical devices described herein may providesuitable vehicles for delivering more than one therapeutic agent to thewall of a vessel. The therapeutic agents may be selected to preventrestenosis through a variety of mechanisms of action to enhance thechance of successful and durable treatment. In some embodiments,different agents may be released at different times so the therapeuticagents may be present in effective concentrations at appropriate timesto act on different biological factors released during the restenosiscascade.

The nanoparticle-coated medical devices described herein may providesuitable vehicles for delivering therapeutic agents that have short invivo half-lives. The nanoparticles may effectively extend the half-lifeof the therapeutic agents. In some embodiments, therapeutic agents thatwould not have previously been used to treat a wall of a vessel due totheir short half-life may be effectively used due to the protectiveeffects of the nanoparticle.

The nanoparticle-coated medical devices described herein may providesuitable vehicles for delivering therapeutic agents that have narrowtherapeutic indices (agents whose effective therapeutic concentrationsare close to their toxic concentrations). The nanoparticles may controlthe release rate of such therapeutic agents to maintain therapeuticconcentrations and avoid toxic levels. Such therapeutic agents may nothave previously been useful for coating on a medical device for whichthe release of the agent may result in doses above a toxicity level.

The nanoparticles may release therapeutic agent following delivery to awall of a vessel over time, in response to a stimuli, or both with thepassage of time and in response to a stimuli.

In one aspect, the present disclosure describes a medical devicecomprising a body having an exterior surface. A coating is disposed onan exterior surface of the medical device. The coating comprises ananoparticle containing a therapeutic agent. The nanoparticle maycomprise a brush-arm star polymer. The medical device may comprise, forexample, an inflatable balloon or a stent on which the coating isdisposed.

In another aspect, the present disclosure described a method fordelivering a therapeutic agent to a tissue of a patient through the useof a medical device coated with a coating comprising a nanoparticlecontaining a therapeutic agent. The method includes delivering a coatedportion of the device to a target location of the patient, thencontacting the coated portion of the device to tissue at the targetlocation to transfer the nanoparticle containing the therapeutic agentto the tissue. The therapeutic agent may be released from thenanoparticle at the tissue, for example, over time or in response to astimulus.

In another aspect, the present disclosure describes a medical deviceincluding an inflatable balloon defining an interior surface and anexterior surface. The interior surface defines an interior space. Acoating is disposed on an exterior surface of the balloon. The coatingcomprises a nanoparticle containing a therapeutic agent. Thenanoparticle may comprise a brush-arm star polymer.

In yet another aspect, the present disclosure described a method fordelivering a therapeutic agent to a tissue of a patient through the useof a medical device having an inflatable balloon coated with a coatingcomprising a nanoparticle containing a therapeutic agent. The methodincludes delivering the inflatable balloon of the device to a targetlocation of the patient, then inflating the inflatable balloon byintroducing a fluid into an interior space of the inflatable balloon tocause the coating to contact tissue at the target location. Inflatingthe balloon causes the balloon to expand against tissue of the patientto transfer the nanoparticle containing the therapeutic agent to thetissue. The therapeutic agent may be released from the nanoparticle atthe tissue, for example, over time or in response to a stimulus.

In some embodiments described herein, a method for coating a medicaldevice comprises applying a coating to an exterior surface of thedevice. The coating comprises a nanoparticle containing a therapeuticagent. The nanoparticle may comprise a brush-arm star polymer.

Advantages and additional features of the subject matter of the presentdisclosure will be set forth in the detailed description which follows,and in part will be readily apparent to those skilled in the art fromthat description or recognized by practicing the subject matter of thepresent disclosure as described herein, including the detaileddescription which follows, the claims, as well as the appended drawings.

It is to be understood that both the foregoing general description andthe following detailed description present embodiments of the subjectmatter of the present disclosure, and are intended to provide anoverview or framework for understanding the nature and character of thesubject matter of the present disclosure as it is claimed. Theaccompanying drawings are included to provide a further understanding ofthe subject matter of the present disclosure, and are incorporated intoand constitute a part of this specification. The drawings illustratevarious embodiments of the subject matter of the present disclosure andtogether with the description serve to explain the principles andoperations of the subject matter of the present disclosure.Additionally, the drawings and descriptions are meant to be merelyillustrative, and are not intended to limit the scope of the claims inany manner.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of specific embodiments of thepresent disclosure can be best understood when read in conjunction withthe following drawings, in which:

FIGS. 1-4 present examples of tissue concentration profiles oftherapeutic agents that may be achieved by various embodiments of coatedballoon catheters described herein;

FIG. 5 is a general reaction scheme for producing a brush-arm starpolymer in accordance with various embodiments described herein;

FIGS. 6-7 are schematic drawings of macro-monomers that may be used toform brush-arm star polymers in accordance with various embodimentsdescribed herein;

FIG. 8 is a schematic drawing of a cross-linker that may be used to formbrush-arm star polymers in accordance with various embodiments describedherein;

FIG. 9-10 are structures of macro-monomers that may be used to formbrush-arm star polymers in accordance with various embodiments describedherein;

FIG. 11 is a structure of a cross-linker that may be used to formbrush-arm star polymers in accordance with various embodiments describedherein;

FIG. 12 is a schematic sectional view of an embodiment of a medicaldevice having a coating comprising a nanoparticle for releasing atherapeutic agent;

FIG. 13 is a schematic sectional view of an embodiment of an inflatableballoon having a coating comprising a nanoparticle for releasing atherapeutic agent;

FIG. 14 is a schematic sectional view of an inflatable balloon catheterin accordance with various embodiments described herein; and

FIGS. 15A-B are schematic views of an inflatable balloon catheter in anartery in uninflated (FIG. 15A) and inflated (FIG. 15B) states inaccordance with various embodiments described herein.

The schematic drawings are not necessarily to scale.

DETAILED DESCRIPTION

Reference will now be made in greater detail to various embodiments ofthe subject matter of the present disclosure, some embodiments of whichare illustrated in the accompanying drawings. Like numbers used in thefigures refer to like components and steps. However, it will beunderstood that the use of a number to refer to a component in a givenfigure is not intended to limit the component in another figure labeledwith the same number. In addition, the use of different numbers to referto components in different figures is not intended to indicate that thedifferent numbered components cannot be the same or similar to othernumbered components.

The present disclosure describes, among other things, a medical deviceon which a coating comprising a nanoparticle containing a therapeuticagent is disposed. The nanoparticle is configured to control the releaseof the therapeutic agent, for example, during a desired time or inresponse to a desired stimulus.

The medical device may be coated with one or more nanoparticles thatcontain one or more therapeutic agents and, optionally, one or moretherapeutic agents that are not included in nanoparticles to achieve adesired tissue concentration of therapeutic agent. The timing of therelease of therapeutic agent, as well as the therapeutic agents used,may be tailored to treatment of a particular disease, such asrestenosis.

FIGS. 1-4 present non-limiting examples of concentration profiles oftherapeutic agents that may be desired following delivery by medicaldevices as described herein. For example, FIG. 1 schematically shows atissue concentration profile of a therapeutic agent 1 that is notassociated with a nanoparticle and a tissue concentration profile of atherapeutic agent 2 released from a nanoparticle. In the embodimentdepicted in FIG. 1, the nanoparticle provides slow release rate oftherapeutic agent. Accordingly, the initial concentration of therapeuticagent available to the tissue may be lower than with the therapeuticagent that is not associated with a nanoparticle. However, thetherapeutic agent in the nanoparticle may remain at effectiveconcentrations for longer than the therapeutic agent that is notassociated with a nanoparticle. For purposes of illustration, a line(EC) that may be indicative of an effective concentration is shown.

Referring now to FIG. 2, tissue concentration profile 1 of a therapeuticagent that is not associated with a nanoparticle and a tissueconcentration profile 2 of a therapeutic agent released from ananoparticle are schematically shown. In the depicted embodiment, thetherapeutic agent released from the nanoparticle (trace 2) and thetherapeutic agent not associated with the nanoparticle (trace 1) are thesame and may be coated on the same balloon. In the depicted embodiment,the cumulative dose of therapeutic agent (sum of available therapeuticagent associated with nanoparticle and not associated with nanoparticle)is shown by schematic trace 4. In the depicted embodiment, release ofthe therapeutic agent from the nanoparticle is delayed. Preferably,substantial release of the therapeutic agent is delayed until thetherapeutic agent not associated with the nanoparticle approachesconcentrations that are near the effective concentration (illustrated byline EC). In the embodiment depicted in FIG. 2, effective concentrationsof therapeutic agent may be maintained in the tissue for a substantiallylonger time than with the use of therapeutic agent not associated withnanoparticle alone. Compare schematic trace 1 (no nanoparticle) toschematic trace 4 (cumulative).

Referring now to FIG. 3, a schematic representation of tissueconcentrations of therapeutic agents released from three differentnanoparticles (1, 2, 3) is shown. The nanoparticles release therapeuticagents at different times, for example in response to a stimulus, suchas light, a magnetic field, or the like. The three differentnanoparticles may contain the same or different therapeutic agents.

Referring now to FIG. 4, another schematic representation of tissueconcentrations of therapeutic agents released from differentnanoparticles is shown is shown. The schematic tissue concentrationprofile shown in trace 1 may be of a therapeutic agent associated with ananoparticle or not associated with a nanoparticle. The schematic tissueconcentration profile shown in trace 2 is of a therapeutic agentassociated with a nanoparticle configured to delay the release of thetherapeutic agent. The schematic tissue concentration profile shown intrace 3 is of a therapeutic agent associated with a nanoparticleconfigured to delay the release of the therapeutic agent even longerthan the nanoparticle associated with trace 2. The therapeutic agent inthe three traces (1, 2, 3) may be the same or different. If thetherapeutic agent is the same, the effective concentration may bemaintained for extended times. If the therapeutic agents are different,release is preferably timed to be most effective for the particularagent in light of the disease being treated.

Any suitable nanoparticle may be employed to control the timing of therelease of the therapeutic agent. In some embodiments, the nanoparticleis configured to slowly release therapeutic agent contained in thenanoparticle over time following delivery of the nanoparticle to tissueof a patient. In some embodiments, the nanoparticle is configured todelay release of therapeutic agent after delivery to a tissue of apatient and then to release the agent slowly over time or in a morequick burst-like manner. In some embodiments, the nanoparticle isconfigured to release therapeutic agent upon exposure to a stimulus,such as light, an electromagnetic field, heat or the like. Once exposedto the stimulus the nanoparticle may be configured to releasetherapeutic agent rapidly, slowly or at a moderate rate.

More than one nanoparticle having one or more of the release propertiesdescribed above may be employed to coat a medical device. One or moretherapeutic agents may be incorporated into one or more of thenanoparticles. Accordingly, temporally controlled release of therapeuticagent following delivery of the nanoparticles to tissue of a patient,such as to a wall of a vessel to treat a stenosis and preventrestenosis, may be achieved.

In some embodiments, the nanoparticle comprises a brush-arm starpolymer. Brush-arm star polymers are described in, for example, Lui etal., J. Am. Chem. Soc. 2012, 134, 16337-16344; Liao et al., J. Am. Chem.Soc. 2014, 136, 5896-5899; and U.S. Patent Application Publication No.2016/0296631, each of which is hereby incorporated herein by referencein their entireties. One or more therapeutic agent may be attached to acomponent of the brush-arm star polymer.

A brush-arm star polymer may be prepared in any suitable manner. Forexample, a brush-arm star polymer may be prepared by polymerizingmacro-monomers. As used herein, a “macro-monomer” is a macromoleculehaving a group that enables it to act as a monomer. Preferably, thepolymerized macromolecules forma bottle-brush polymer having a livingchain end. A plurality of bottle-brush polymer having a living chainends may be connected by cross-linkers to a brush-arm star polymer. Sucharm-first polymerization may enable synthesis of star polymers havingmoieties that are incompatible with radical polymerization. See, forexample, Lui et al., J. Am. Chem. Soc. 2012, 134, 16337-16344.

Referring now to FIG. 5, one or more macro-monomers 10, 20 may bepolymerized in the presence of a catalyst to produce a bottle-brushpolymer having a living chain ends 30. Multiple bottle-brush polymershaving living chain ends 30 may be connected with one or morecross-linkers to form a brush-arm star polymer 40.

Referring now to FIG. 6, a schematic example of a macro-monomer 10 thatmay be employed to form a brush-arm star polymer is shown. Themacro-monomer 10 may include a monomer moiety 12 and a cleavable linker14 attaching a therapeutic agent 16 to the monomer moiety 12. Themacro-monomer 10 may also include one or more polymers 18 attached tothe monomer moiety 12; e.g., via a linker (not shown).

Referring now to FIG. 7, a schematic example of another macro-monomer 20that may be employed to form a brush-arm star polymer is shown. Themacro-monomer 20 may include a monomer moiety 22 and a linker 24, whichmay optionally be a cleavable linker, attaching a polymer 28 to themonomer moiety 22.

Referring now to FIG. 8, a schematic example of a cross-linker 50 thatmay be employed to form a brush-arm star polymer is shown. Thecross-linker 50 comprises two or more monomer moieties 52, 59 joined bya linker 54, which may optionally be a cleavable linker.

The macro-monomers 10, 20 and the cross-linker 50 may, independently,include any suitable monomer moiety 12, 22, 52, 59. In some embodiments,the monomer moiety 12, 22, 52, 59 comprises a monomer moiety capable ofbeing polymerized via ring-opening metathesis polymerization. Forexample, the monomer moiety 12, 22, 52, 59 may comprise a norbornenemoiety.

Preferably, the polymers 18, 28 of the macro-monomers 10, 20 arehydrophilic. In some embodiments, the polymers 18, 28 comprisepolyethylene glycol (PEG).

The cleavable linker 14 of the macro-monomer 10 may be any suitablecleavable linker. Upon cleavage of the cleavable linker 14, thetherapeutic agent 16 may be released to act on tissue. For example, thecleavable linker 14 may be a linker cleaved by hydrolysis (such as anester linkage), a photocleavable linker, a temperature sensitive linker,a magnetic field-induced cleavable linker, or the like. The cleavablelinkers 14 cleavable by hydrolysis may cleave over time when exposed tobodily fluids, such as when delivered to a tissue of a patient. Light,heat, magnetic fields, or the like may be applied within the body orexternal to the body to cleave the linker. If the stimulus is appliedexternal to the body, a sufficient amount of energy from the stimulus tocleave the linker should reach the location in which the nanoparticle isdelivered.

Other linkers 24, 54 may, or may not, be cleavable. Preferably, thelinker 54 of the cross-linker 50 is cleavable.

Some more specific examples of the macro-monomers 10, 20 and thecross-linkers 50 are shown in FIGS. 9-11. The macro-monomer 10 shown inFIG. 9 includes a norbornene monomer moiety 12 and a therapeutic agent16, in this case paclitaxel, linked to the monomer moiety 12 via acleavable linker. The linker may be cleaved at the indicated cleavagesite 15 via hydrolysis to release the paclitaxel. The macro-monomer 10also includes a polymer moiety 18, in this case PEG. For themacro-monomer 10 depicted in FIG. 9, x, y and z may be any suitableinteger. For example, y may be an integer from 1 to 10, inclusive. Insome embodiments, y is 6. Z may be an integer from 1 to 5, inclusive. Insome embodiments, z is 3. X may be an integer from 30 to 100, inclusive.In some embodiments, x is 68. A macro-monomer 10 as depicted in FIG. 9may be synthesized in any suitable manner. For example, the molecule maybe synthesized as described in Liao et al., J. Am. Chem. Soc. 2014, 136,5896-5899 in which paclitaxel is substituted for camptothecin, or may besynthesized in accordance with the teachings of U.S. Patent ApplicationNo. Publication 2016/0296631.

The macro-monomer 20 shown in FIG. 10 includes a norbornene monomermoiety 22 and a polymer 18, in this case PEG, linked to the monomermoiety 12 via a linker 24. For the macro-monomer 20 depicted in FIG. 10,x may be any suitable integer. X may be an integer from 30 to 100,inclusive. In some embodiments, x is 68. A macro-monomer 20 as depictedin FIG. 10 may be synthesized in any suitable manner. For example, themolecule may be synthesized as described in Liao et al., J. Am. Chem.Soc. 2014, 136, 5896-5899 or in U.S. Patent Application No. Publication2016/0296631.

The cross-linker 50 shown in FIG. 11 includes first 52 and second 59norbornene monomer moieties connected by the linker 54. The depictedlinker 54 is a cleavable linker that may be cleaved at cleavage site 55or 57 by hydrolysis. A cross-linker 50 as depicted in FIG. 11 may besynthesized in any suitable manner. For example, the molecule may besynthesized as described in Liao et al., J. Am. Chem. Soc. 2014, 136,5896-5899 or in U.S. Patent Application Publication No. 2016/0296631.

In some embodiments, the macro-monomers 10 and 20 depicted in FIGS. 9-10are polymerized via the norbornene moieties by ring-opening metathesispolymerization to produce bottle brush polymers having a living chainend and the bottle brush polymers are joined by the cross-linkers 50depicted in FIG. 11 to produce a paclitaxel-containing brush-arm starpolymer that may be coated on a medical device. The ratios of themacro-monomer 10, the macro-monomer 20, and the cross-linker 50 may becontrolled to achieve desired release rates and timing. For example,higher cross-linker 50 proportions may delay or slow the release ofpaclitaxel relative to lower proportions of the cross-linker 50.

It will be understood that the compounds depicted in FIGS. 9-11 aremerely for purposes of example and not limitation. Other suitablecompounds that may be employed to produce suitable brush-arm starpolymers are described in, for example, U.S. Patent ApplicationPublication No. 2016/0296631.

The nanoparticles may comprise any suitable therapeutic agent. Forpurposes of the present disclosure, a diagnostic agent, such as acontrast agent or a dye, is a “therapeutic agent.” A coating asdescribed herein may include, for example, one or more of ananti-proliferative agent, an antibiotic, an anti-mitotic agent or thelike. It will be understood and appreciated that some agents may havemore than one therapeutic or diagnostic action. Preferably, ananoparticle as described herein includes an anti-restenosis agent. Forexample, a coating may include one or more of paclitaxel, rapamycin,everolimus, zotarolimus, and the like.

Other examples of therapeutic agents that may be included in ananoparticle for coating on an inflatable balloon are one or more ofheparin or another thrombin inhibitor, hirudin, hirulog, argatroban,D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone or anotherantithrombogenic agent, or mixtures thereof; urokinase, streptokinase, atissue plasminogen activator, or another thrombolytic agent, or mixturesthereof; a fibrinolytic agent; a calcium channel blocker, a nitrate,nitric oxide, a nitric oxide promoter or another vasodilator; anantimicrobial agent or antibiotic; aspirin, ticlopdine or anotherantiplatelet agent; colchicine or another antimitotic, or anothermicrotubule inhibitor; cytochalasin or another actin inhibitor; aremodeling inhibitor; deoxyribonucleic acid, an antisense nucleotide oranother agent for molecular genetic intervention; GP IIb/IIIa, GP Ib-IXor another inhibitor or surface glycoprotein receptor; methotrexate oranother antimetabolite or antiproliferative agent; an anticancerchemotherapeutic agent; dexamethasone, dexamethasone sodium phosphate,dexamethasone acetate or another dexamethasone derivative, or anotheranti-inflammatory steroid; dopamine, bromocriptine mesylate, pergolidemesylate or another dopamine agonist; a radiotherapeutic agent; apeptide, a protein, an enzyme, an extracellular matrix component, acellular component or another biologic agent; captopril, enalapril oranother angiotensin converting enzyme (ACE) inhibitor; alphatocopherol,superoxide dismutase, deferoxyamine, a 21-aminosteroid (lasaroid) oranother free radical scavenger, iron chelator or antioxidant; andangiopeptin.

Unless content clearly dictates otherwise, general reference to atherapeutic agent in the present disclosure includes reference to saltsof the agent, hydrates of the agent, polymorphs of the agent, isomers ofthe agent (including constitutional isomers and stereoisomers such asenantiomers and diasteriomers), and the like.

More than one therapeutic agent may be employed in the same or differentnanoparticles to achieve release profiles as desired. In someembodiments, the same therapeutic agent is associated with differentnanoparticles.

In some embodiments, one or more therapeutic agents that are notassociated with a nanoparticle may be coated on a medical device. Forexample, any one or more of the therapeutic agents described above maybe coated on the medical device. In some embodiments, a coating of amedical device comprises both paclitaxel and a paclitaxel-containingnanoparticle. The paclitaxel that is not associated with a nanoparticlemay be available for immediate or near immediate release when contactedwith tissue of a patient, while the paclitaxel associated with thenanoparticles may have a delayed or slower release rate.

The coating preferably comprises one or more therapeutic agents, whetherassociated with a nanoparticle or not, in a therapeutically effectiveamount. As used herein, “therapeutically effective amount” means anagent in an amount capable of inducing a therapeutic or preventiveeffect against the disease being treated or prevented. For example, ifthe disease being treated or prevented is restenosis of vascular tissue,the one or more agents present in the coating may be present in anamount effective to treat or prevent restenosis of the treated vasculartissue in the patient.

In some embodiments, the coating comprises one or more of zotarolimus,sirolimus, dexamethasone and paclitaxel.

Preferably, the coating comprises paclitaxel and is used to treat orprevent restenosis. In some embodiments, at least some or all of thepaclitaxel is in anhydrous crystalline form. The coating provides forrelease and bioavailability of a therapeutically effective amount ofpaclitaxel when the coating contacts tissue at the site of intervention.Preferably, the coating provides for release from the medical devicesurface in periods of time less than 2 minutes, preferably between 30seconds and 1 minute, and an absorption by the vascular tissue inperiods of time ranging between 1 second and 25 minutes, preferablybetween 20 seconds and 25 minutes.

As used herein, “site of intervention” means the section of the bloodvessel treated directly with a medical device described herein, and theadjacent portion in the tissues of which the post-procedure presence ofpaclitaxel can be detected. Generally, such section will extend up to 10mm down- and upstream from the contact section with the coated medicaldevice.

In some embodiments, a coating comprising paclitaxel that is notassociated with a nanoparticle also comprises urea. The presence of ureain a paclitaxel-containing coating may promote the release of thepaclitaxel. Paclitaxel may be dissolved in an appropriate solvent in thepresence of urea and coated on the medical device, on another coatinglayer on the medical device, or mixed with other coating components andcoated on the medical device. Urea may be present in any suitableamount, such as from 1 mg per mL to 100 mg per mL solvent. In someembodiments, a layer of paclitaxel and urea are coated directly on themedical device or are coated on another layer of the coating.

The coating may include any suitable number of layers. The therapeuticagent-containing nanoparticles and optional therapeutic agent notassociated with a nanoparticle may be intermixed with other componentsof the coating and applied as a single layer. In some embodiments, alayer comprising therapeutic agent-containing nanoparticles is appliedto the medical device and a layer, such as a polymeric layer, is appliedon top of the nanoparticle-containing layer. In some embodiments, alayer, for example comprising a polymer, is applied to the medicaldevice and a layer comprising the nanoparticles is applied on top of thepreviously applied layer.

In general, a coating layer may be disposed on the medical device or ona coating layer disposed on the medical device in any suitable manner.For example, a solution comprising the components of the layer, such asthe nanoparticle or a therapeutic agent not associated with ananoparticle, may be coated on the medical device by dipping the medicaldevice in the solution, the solution may be sprayed on the medicaldevice, or the solution may be deposited on the inflatable balloon with,for example, a syringe, micropipette, or other similar dispensingdevice.

If the medical device comprises, for example, an inflatable balloon oran expandable stent, the solution may be applied when the inflatableballoon is inflated or the stent is expanded, or when the balloon is ina folded condition or the sent is contracted. If the medical devicecomprises an inflatable balloon and the coating is applied when theinflatable balloon is in the folded condition, the solution maypenetrate under the folds by capillary action or may be applied by, forexample, micro-nozzles under the folds. It the medical device comprisesa stent, the stent may be coated by filling the stent via capillaryaction as described in, for example, U.S. Patent Application PublicationNo. 2013/0284310 or may be coated in any other suitable manner.

One or more coatings of the solution may be applied to the medicaldevice or other coating layer. The solvent may be allowed to evaporateunder ambient conditions, under heated conditions, under vacuum drying,or heating and vacuum drying. The medical device or underlying coatinglayer may be fully or partially coated with the layer or subsequentlayer.

The coatings described herein may be applied to any suitable medicaldevice. Preferably, the medical device comprises a coated portiondeliverable through a blood vessel of a patient. For example, themedical device may comprise an inflatable balloon or a stent, such as aself-expanding stent or a balloon expandable stent. The medical devicemay comprise a balloon catheter comprising an inflatable balloon.

Any suitable inflatable medical inflatable balloon may be coated with ananoparticle coating described herein. The inflatable balloons may becompliant, semi-compliant or non-compliant. The inflatable balloons maybe formed from any suitable material. For example, the inflatableballoons may be formed of polyamides, polyethylene terephathalate (PET),polyurethane, latex, silicone, polyethylene (PE), polypropylene (PP),polyetherimide (PEI), polytetrafluoroethylene (PTFE), ethylenetetrafluoroethylene (ETFE), fluorinated ethylene propylene (FEP),polyoxymethylene (POM), polybutylene terephthalate (PBT),polyether-block-ester, polyvinylchloride (PVC), polyether-block-amide,polyetheretherketone (PEEK), polyimide (PI), polyphenylene sulfide(PPS), polyphenylene oxide (PPO), poly(ethylenenaphthalenedicarboxylate) (PEN), polysulfone, perfluoro(propyl vinylether) (PFA), or mixtures, combinations, copolymers thereof, and thelike.

The inflatable balloon will typically have a length of at least 1 cm to50 cm, preferably being in a range from about 1.5 cm to 20 cm, and mayhave inflated diameters in a range from 1.5 mm to about 20 mm, forinstance 1.5 mm to 5 mm, but may be of any suitable size.

An inflatable balloon catheter comprising a coated inflatable balloon asdescribed herein may be used for any suitable purpose. In preferredembodiments, the inflatable balloon catheter is an intravascularinflatable balloon catheter. For example, the inflatable ballooncatheter may be an angioplasty catheter or a stent delivery catheter.Preferably, the inflatable balloon catheter is an angioplasty catheter.Preferably, the inflatable balloon catheter is used for treatment ofrestenosis in an artery.

In use, the inflatable balloon may be inflated by infusing fluid, suchas water, saline or the like, into the inflatable balloon through, forexample, a lumen of a catheter in communication with the interiorsurface of the inflatable balloon.

Any suitable implantable medical stent may be coated with a nanoparticlecoating described herein. The sent may comprise a frame comprising oneor more of a variety of biocompatible metals such as stainless steel,titanium, magnesium, aluminum, chromium, cobalt, nickel, gold, iron,iridium, chromium/titanium alloys, chromium/nickel alloys,chromium/cobalt alloys, such as MP35N and L605, cobalt/titanium alloys,nickel/titanium alloys, such as nitinol, platinum, and platinum-tungstenalloys. The metal composition gives the stent framework the mechanicalstrength to support the lumen wall of the vessel and sufficientlongitudinal flexibility so that it can be transported through thecardiovascular system.

The stent may comprise a polymeric frame that may be biodegradable,biostable, or comprise a mixture of polymeric materials that are bothbiostable and biodegradable. Biodegradable polymers appropriate for thestents include polylactic acid, polyglycolic acid, and their copolymers,caproic acid, polyethylene glycol, polyanhydrides, polyacetates,polycaprolactones, poly(orthoesters), polyamides, polyurethanes andother suitable polymers. Biostable polymers appropriate for the stentsinclude polyethylene, polypropylene, polymethyl methacrylate,polyesters, polyamides, polyurethanes, polytetrafluoroethylene (PTFE),polyvinyl alcohol, and other suitable polymers. These polymers may beused alone or in various combinations to give the stent uniqueproperties such as controlled rates of degradation.

The stent frame may be formed by shaping a metallic wire or polymericfilament, or by laser cutting the stent from a metallic or polymericsheet, or any other appropriate method. The surface of the stentframework may be cleaned by washing with surfactants to remove oils,mechanical polishing, electropolishing, etching with acid or base, orany other effective means to expose a clean, uniform surface that isready for applying a coating.

The coating may include a polymer matrix comprising biodegradablepolymers such as polylactic acid, polyglycolic acid, and theircopolymers, caproic acid, polyethylene glycol, polyanhydrides,polyacetates, polycaprolactones, poly(orthoesters), polyamides,polyurethanes and other suitable polymers. The therapeuticagent-containing nanoparticles may be incorporated within the polymericmatrix, applied to the polymeric matrix, or the like. The coating maycomprise one or more layer, such as described above.

The sent may be balloon-expandable or self-expanding. The coated stentmay be positioned within a vessel through the use of a catheter to whichthe stent is coupled. The catheter may comprise an inflatable balloonthat may be inflated to expand the stent such that the stent contacts awall of the vessel, the balloon may be deflated, and the catheterremoved leaving the stent in place. The catheter may include a sheaththat retracts to enable expansion of a self-expanding stent to contact awall of the vessel. When the sheath is fully retracted, the catheter maybe removed from the vessel, leaving the stent in place.

Referring now to FIG. 12, a sectional view of a medical device 400 isshown. The medical device 400 comprises a body 410 having exteriorsurface 404. A coating 200 is disposed on the exterior surface 404 ofthe medical device 400. The coating 200 comprises a therapeuticagent-containing nanoparticle and may optionally comprise one or morepolymers to assist in controlling the release of the nanoparticles orprotecting the nanoparticles during the delivery process (such asnavigating the device through the vasculature). The coating 200 mayoptionally comprise a therapeutic agent that is not associated with ananoparticle. The coating 200 may comprise one or more additional layers(not shown). The body 410 may define an interior surface 102 defining aninterior space 105. The device 400 may be or comprise an inflatableballoon or a stent.

Referring now to FIG. 13, a sectional view of an inflated inflatableballoon 100 is shown. The inflatable balloon 100 comprises a wall 110defining an interior surface 102 and an exterior surface 104, theinterior surface 104 defining an interior space 105. A coating 200 isdisposed on the exterior surface 104 of the inflatable balloon 100. Thecoating 200 comprises a therapeutic agent-containing nanoparticle andmay optionally comprise one or more polymers to assist in controllingthe release of the nanoparticles or protecting the nanoparticles duringthe delivery process (such as navigating the balloon through thevasculature). The coating 200 may optionally comprise a therapeuticagent that is not associated with a nanoparticle. The coating 200 maycomprise one or more additional layers (not shown).

Referring now to FIG. 14, a sectional view of an inflatable ballooncatheter 300 is shown. The inflatable balloon catheter 300 includes acatheter 310 and an inflatable balloon 100 having a wall 110 defining aninterior surface 102 and an exterior surface 104 (as shown in FIG. 13),the interior surface 102 defining an interior space 105. A coating 200,such as a coating described above regarding FIG. 13 is disposed on theexterior surface 104 defined by the inflatable balloon wall 110. Thecatheter 310 defines a lumen 305 in communication with the interiorspace 105 of the inflatable balloon 100 for inflating the inflatableballoon 100.

Referring now to FIGS. 15A-B, schematic drawings showing an inflatableballoon catheter 300 in a vessel 400 in uninflated (FIG. 15A) andinflated (FIG. 15B) states are shown. The inflatable balloon catheter300 may be advanced within the vessel 400, such as an artery, untilinflatable balloon 100 is aligned with a target site for intervention,such as a narrowing of the artery 400. The inflatable balloon 100 may beinflated (FIG. 15B) with fluid. Contact of the coating (not shown)disposed on the balloon with a wall of the artery 400 results intransfer of the coating 200 having the nanoparticles from the balloon100 to the wall of the artery 400.

While described herein mainly in terms of treatment of restenosis inarteries, the balloon catheters described herein may be useful fortreating other diseases in other passageways. For example, the ballooncatheters described herein may be used in veins, coronary arteries,renal arteries, peripheral arteries including illiac arteries, arteriesof the neck and cerebral arteries, and may also be advantageouslyemployed in other body structures, including but not limited toarteries, veins, biliary ducts, urethras, fallopian tubes, bronchialtubes, the trachea, the esophagus and the prostate.

All scientific and technical terms used herein have meanings commonlyused in the art unless otherwise specified. The definitions providedherein are to facilitate understanding of certain terms used frequentlyherein and are not meant to limit the scope of the present disclosure.

As used herein, singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to a “layer” includes examples having two or moresuch “layers” unless the context clearly indicates otherwise.

As used in this specification and the appended claims, the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise. The term “and/or” means one or all of thelisted elements or a combination of any two or more of the listedelements.

The words “preferred” and “preferably” refer to embodiments of thedisclosure that may afford certain benefits, under certaincircumstances. However, other embodiments may also be preferred, underthe same or other circumstances. Furthermore, the recitation of one ormore preferred embodiments does not imply that other embodiments are notuseful, and is not intended to exclude other embodiments from the scopeof the inventive technology.

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatany particular order be inferred. Any recited single or multiple featureor aspect in any one claim can be combined or permuted with any otherrecited feature or aspect in any other claim or claims.

As used herein, “providing” in the context of providing an article foruse in a method means to make, purchase, or otherwise obtain thearticle.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to the present inventivetechnology without departing from the spirit and scope of thedisclosure. Since modifications, combinations, sub-combinations andvariations of the disclosed embodiments incorporating the spirit andsubstance of the inventive technology may occur to persons skilled inthe art, the inventive technology should be construed to includeeverything within the scope of the appended claims and theirequivalents.

1-34. (canceled)
 35. A medical device comprising: a body having anexterior surface; and a coating disposed on the exterior surface of thebody, the coating comprising a therapeutic agent-containingnanoparticle, wherein the nanoparticle comprises a brush-arm starpolymer, wherein the therapeutic agent of the therapeuticagent-nanoparticle comprises an antiproliferative agent, and wherein thecoating further comprises a second therapeutic agent that is notassociated with the nanoparticle.
 36. The medical device of claim 35,wherein the second therapeutic agent comprises an anti-inflammatorysteroid.
 37. The medical device of claim 36, wherein theanti-inflammatory steroid is dexamethasone, dexamethasone sodiumphosphate, or dexamethasone acetate.
 38. The medical device of claim 35,wherein the second therapeutic agent comprises an anti-proliferativeagent different than the antiproliferative agent of the nanoparticle.39. The medical device of claim 38, wherein the second therapeutic agentcomprises paclitaxel, rapamycin, everolimus, or zotarolimus.
 40. Themedical device of claim 39, wherein the second therapeutic agentcomprises paclitaxel.
 41. The medical device of claim 40, wherein thecoating further comprises urea.
 42. The medical device of claim 35,wherein the therapeutic agent of the therapeutic agent-nanoparticlecomprises paclitaxel, rapamycin, everolimus, or zotarolimus.
 43. Themedical device of claim 35, wherein the therapeutic agent of thetherapeutic agent-nanoparticle comprises paclitaxel.
 44. The medicaldevice of claim 35, wherein the coating further comprises a secondtherapeutic agent-containing nanoparticle comprising ananti-inflammatory steroid and a brush-arm star polymer.
 45. The medicaldevice of claim 35, wherein the nanoparticle comprises a cleavablelinker attaching the therapeutic agent to the nanoparticle.
 46. Themedical device of claim 45, wherein the cleavable linker is a linkercleavable by hydrolysis.
 47. The medical device of claim 46, wherein thecleavage linker comprises an ester bond.
 48. The medical device of claim35, wherein the nanoparticle is formed by polymerization of one or moremacro-monomers, at least one of which comprises the therapeutic agent,to form bottle-brush polymers having a living chain end, and connectingthe bottle-brush polymers having a living chain end with a cross-linkerto form the brush-arm star polymer nanoparticle.
 49. The medical deviceof claim 35, wherein the body comprises a stent.
 50. The medical deviceof claim 35, wherein the body comprises an inflatable balloon definingan interior surface, wherein the interior surface defines an interiorspace.
 51. A method comprising: providing a medical device according toclaim 35; inserting the medical device to the target location of apatient; and contacting the medical device to tissue at the targetlocation, wherein contacting the medical device to the tissue causes thetherapeutic agent-containing nanoparticle and the second therapeuticagent to be transferred to the tissue.
 52. The method of claim 51,wherein the tissue of the patient to which the nanoparticle istransferred is a wall of an artery.
 53. A medical device comprising: aninflatable balloon having an exterior surface; and a coating disposed onthe exterior surface of the inflatable balloon, the coating comprising apaclitaxel-containing nanoparticle, wherein the nanoparticle comprises abrush-arm star polymer, and wherein the coating further comprises asecond therapeutic agent that is not associated with the nanoparticle.54. The medical device of claim 53 wherein the coating further comprisesurea.
 55. The medical device of claim 53 wherein the second therapeuticagent is selected from the group containing dexamethasone, dexamethasonesodium phosphate, dexamethasone acetate, rapamycin, everolimus, orzotarolimus.